SYSTEMATIC REVIEW
published: 03 May 2022
doi: 10.3389/fcvm.2022.849201
Edited by:
Maria Lucia Narducci,
Catholic University of the Sacred
Heart Rome, Italy
Reviewed by:
Giannis G. Baltogiannis,
Vrije University Brussel, Belgium
Josef Kautzner,
Institute for Clinical and Experimental
Medicine (IKEM), Czechia
Marek Sramo,
Institute for Clinical and Experimental
Medicine (IKEM), Czechia
*Correspondence:
Stefania Volpe
stefania.volpe@ieo.it
orcid.org/0000-0003-0498-2964
†These authors share last authorship
Specialty section:
This article was submitted to
Cardiac Rhythmology,
a section of the journal
Frontiers in Cardiovascular Medicine
Received: 05 January 2022
Accepted: 22 March 2022
Published: 03 May 2022
Citation:
Franzetti J, Volpe S, Catto V,
Conte E, Piccolo C, Pepa M,
Piperno G, Camarda AM, Cattani F,
Andreini D, Tondo C,
Jereczek-Fossa BA and
Carbucicchio C (2022) Stereotactic
Radiotherapy Ablation and Atrial
Fibrillation: Technical Issues
and Clinical Expectations Derived
From a Systematic Review.
Front. Cardiovasc. Med. 9:849201.
doi: 10.3389/fcvm.2022.849201
Stereotactic Radiotherapy Ablation
and Atrial Fibrillation: Technical
Issues and Clinical Expectations
Derived From a Systematic Review
Jessica Franzetti1,2, Stefania Volpe1,2*, Valentina Catto3,4, Edoardo Conte5,
Consiglia Piccolo6, Matteo Pepa1, Gaia Piperno1, Anna Maria Camarda1,2,
Federica Cattani6, Daniele Andreini5,7, Claudio Tondo3,8,
Barbara Alicja Jereczek-Fossa1,2† and Corrado Carbucicchio3†
1 Department of Radiation Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy, 2 Department of Oncology
and Hemato-Oncology, University of Milan, Milan, Italy, 3 Department of Clinical Electrophysiology and Cardiac Pacing,
Centro Cardiologico Monzino IRCCS, Milan, Italy, 4 Department of Electronics, Information and Biomedical Engineering,
Politecnico di Milano, Milan, Italy, 5 Cardiovascular Computed Tomography and Radiology Unit, Centro Cardiologico
Monzino IRCCS, Milan, Italy, 6 Unit of Medical Physics, European Institute of Oncology (IEO) IRCCS, Milan, Italy,
7 Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milan, Milan, Italy, 8 Department of Biomedical,
Surgical and Dental Sciences, University of Milan, Milan, Italy
Aim: The purpose of this study is to collect available evidence on the feasibility
and efficacy of stereotactic arrhythmia radio ablation (STAR), including both photon
radiotherapy (XRT) and particle beam therapy (PBT), in the treatment of atrial fibrillation
(AF), and to provide cardiologists and radiation oncologists with a practical overview on
this topic.
Methods: Three hundred and thirty-five articles were identified up to November 2021
according to preferred reporting items for systematic reviews and meta-analyses criteria;
preclinical and clinical studies were included without data restrictions or language
limitations. Selected works were analyzed for comparing target selection, treatment plan
details, and the accelerator employed, addressing workup modalities, acute and long-
term side-effects, and efficacy, defined either by the presence of scar or by the absence
of AF recurrence.
Results: Twenty-one works published between 2010 and 2021 were included.
Seventeen studies concerned XRT, three PBT, and one involved both. Nine studies
(1 in silico and 8 in vivo; doses ranging from 15 to 40 Gy) comprised a total of 59
animals, 12 (8 in silico, 4 in vivo; doses ranging from 16 to 50 Gy) focused on humans,
with 9 patients undergoing STAR: average follow-up duration was 5 and 6 months,
respectively. Data analysis supported efficacy of the treatment in the preclinical setting,
whereas in the context of clinical studies the main favorable finding consisted in the
detection of electrical scar in 4/4 patients undergoing specific evaluation; the minimum
dose for efficacy was 25 Gy in both humans and animals. No acute complication was
recorded; severe side-effects related to the long-term were observed only for very
high STAR doses in 2 animals. Significant variability was evidenced among studies in
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May 2022 | Volume 9 | Article 849201
Franzetti et al.
Stereotactic Ablation for Atrial Fibrillation
the definition of target volume and doses, and in the management of respiratory and
cardiac target motion.
Conclusion: STAR is an innovative non-invasive procedure already applied for
experimental treatment of ventricular arrhythmias. Particular attention must be paid
to safety, rather than efficacy of STAR, given the benign nature of AF. Uncertainties
persist, mainly regarding the definition of the treatment plan and the role of the target
motion. In this setting, more information about the toxicity profile of this new approach
is compulsory before applying STAR to AF in clinical practice.
Keywords: systematic review, stereotactic arrhythmia radio ablation (STAR), atrial fibrillation, arrhythmias,
stereotactic body radiotherapy (SBRT), particle beam radiotherapy, target motion
INTRODUCTION
Atrial fibrillation (AF) is one of the most common cardiac
arrhythmias, with an estimated number 8.8 million of affected
subjects in Europe. As the prevalence of AF increases with
age, it is expected to affect approximately 18 million in the
European Union by 2060 (1) and more than 8 million people
in the United States by 2050 (2). In addition, the incidence
of AF increases in patients with cancer having an incidence
of 3.7 per 1,000 person year, also due to medical oncology
treatments (3).
Despite being benign in nature, AF represents a well-
recognized independent risk factor for stroke (4) and has been
associated with potentially severe medical conditions including
heart disease (5) and chronic kidney disease (6). Moreover, a
substantial proportion of eligible patients are undertreated with
medical therapy (7) and 74.6% of the patients (5) are symptomatic
despite ongoing medical therapy. Drugs can also have significant
side effects such as an increased risk of bleeding; all these features
determine a worsened quality of life in patients with AF (8). Based
on the presentation, duration, and spontaneous termination
of AF episodes, five types of AF can be distinguished: first
diagnosed, paroxysmal (self-terminating, in most cases within
48 h), persistent, long-standing persistent (continuous AF lasting
for ≥1 year), and permanent AF (AF that is accepted by the
patient and physician) (9). As AF frequently originates from
an electric trigger located in the pulmonary veins, this site is
the main therapeutic target of an ablation procedure defined
as “pulmonary veins isolation” (PVI) (10). Based on further
empirical evidence, the left-posterior atrial wall has been added to
this target (11). A wide variety of approaches for PVI, including
point-by-point radiofrequency ablation or cryoballoon ablation
(9), has been described. Recently, pulsed-field ablation has been
Abbreviations: 4DCT, four-dimensional computed tomography; AF, atrial
fibrillation; BED, biological effective dose; CK, Cyberknife; CLA, conventional
linear accelerator; IMPT, intensity-modulated proton therapy; LPW, left posterior
wall; MOSFET, metal oxide semiconductor field effect transistor; MRI, magnetic
resonance imaging; MRI-Linac, MRI-linear accelerator; PBT, particle beam
therapy; PET, positron emission tomography; PRISMA, preferred reporting items
for systematic reviews and meta-analyses; PVA, pulmonary vein antra; PVI,
pulmonary vein isolation; RBE, relative biological effectiveness; RSPV-LAJ, right
superior pulmonary vein-left atrial junction; SR, sinus rhythm; STAR, stereotactic
arrhythmia radio ablation; TV, target volume; VMAT, volumetric modulated arc
therapy; VT, ventricular tachycardia; WACA, wide-area circumferential ablation;
XRT, photon radiotherapy.
introduced as an innovative technique for the ablation of AF.
It is based on the induction of cell death by the electric field
(electroporation), has shown good preliminary results in terms
of safety and efficacy (12, 13). Overall, the efficacy of these
procedures reaches 70% in patients with paroxysmal AF and
50% in those with persistent AF (14), while the percentage of
severe related complications approximates 3.5% (15). In addition,
a significant proportion of patients require more than one
procedure to achieve the permanent restoration of sinus rhythm
(SR) (16).
While
alternative
techniques
are
available,
including
ethanol,
needle,
and
bipolar
ablation,
they
are
not
without
disadvantages
or
side
effects,
including
the
uncertainty
of
properly
and
completely
damaging
the
target
(17),
cardiac
perforation
and
tamponade
(18),
or
the
inability
to
appropriately
hit
deep
and
large
substrates (19).
Other than the well-known applications in cancer, radiation
therapy has been used for the treatment of benign medical
conditions, showing both satisfactory efficacy and a good safety
profile (20–22).
In the last 5 years, multiple studies have investigated the
potential of stereotactic arrhythmia radio ablation (STAR):
most of the literature is about the treatment of recurrent
ventricular tachycardia (VT) and involves both conventional
linear accelerator (CLA) (23, 24) and radiosurgery Cyberknife
R⃝
(CK, Accuray, Sunnyvale, CA, United States) accelerator (25–27).
The safety and efficacy of this new therapeutic opportunity seem
to be good in both cases. Moreover, some preclinical studies (28,
29) have used particle beam therapy (PBT) for cardiac ablation:
being able to selectively spare the most critical structures is a clear
advantage and might arguably open up to the future possibility of
re-irradiations.
An increasing body of literature has focused on intracardiac
malignancies undergoing stereotactic radiosurgery, and on
its possible related side effects (30–32). Similarly, dosimetric
studies on heart irradiation have been published in the last
years (33, 34). A significant issue of cardiac radiosurgery
may be the long-term effects of radiation on myocardial,
conduction, valvular, and other cardiac tissues. These concerns
can be at least partially addressed by the study of long-
term toxicity in lymphoma (35) and centrally located lung
treatment (36).
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Stereotactic Ablation for Atrial Fibrillation
Although photons are the most known form of energy in
radiation therapy, PBT (both heavy ions and protons) are an
emerging alternative to conventional treatments. Advantages
of this form of radiotherapy are the favorable physical
characteristics and the major relative biological effectiveness
(RBE), especially when referring to carbon ion radiotherapy (37).
As a consequence, studies favoring the role of stereotactic PBT
have been developed (38) over the last couple of years.
Given the lack of comparable works, this article aims to review
the current evidence on the feasibility and efficacy of external
beam radiotherapy for AF and to provide radiation oncologists
and cardiologists with a practical overview of this theme.
MATERIALS AND METHODS
In compliance with the preferred reporting items for systematic
reviews and meta-analyses (PRISMA) (39, 40), literature research
was performed in November 2021.
Articles were researched in multiple database sources:
NCBI PubMed, EMBASE, PMID, and Scopus. The strings of
research employed and the PRISMA’s checklist are available in
Supplementary Material 1. The PRISMA flow diagram for article
selection is illustrated in Figure 1.
Both preclinical and clinical studies were considered; no data
restrictions or language limitations were applied. The inclusion of
gray literature was allowed. Studies whose focus were other forms
of arrhythmias (i.e., ventricular and nodal) were considered out
of the scope of this work and were therefore excluded.
An independent re-assessment was performed by a second
reviewer; in case of any disagreement, a third reviewer
was engaged. Selected works were independently screened
by two reviewers; whenever disagreement occurred regarding
the inclusion criteria, a third reviewer was called to resolve
the discrepancy.
Summary and definition of the radiation oncology-related
terms are available in Supplementary Material 2.
RESULTS
Following reviewing and duplicate removal, a total of 21 articles
presented from 2010 to 2021 was included in the analysis.
They consisted of one and 8 preclinical studies on treatment
plans for animals and humans treatments, respectively, 8
preclinical studies on animal models, and 4 clinical studies on
human subjects. Here follows an overview of selected articles,
categorized according to the above-mentioned criteria.
Preclinical Studies
Animals Subjects
The first study on the in vivo cardio ablation for AF was
performed in 2010 by Sharma et al. (41). Overall, preclinical
studies were conducted on healthy animals subjects, with 26
mini-pigs; in only 3 studies also canines were considered (42–
44), for a total number of 27 cases (Table 1). Average or median
doses could not be calculated for preclinical works due to a lack
of information in some of the included studies.
In most cases, animals underwent general anesthesia and
received ablation in a single fraction delivered by CK. For
treatments delivered by CK, fiducials (both gold seeds and
catheter tips) were necessary to evaluate target motion. A CLA
was used in 3 cases (44–46). In almost all the articles, both cardiac
and respiratory motions were considered, except for Chang
et al. (44) who acquired four-dimensional computed tomography
(4DCT) only in case of the large respiratory amplitude of the
animal, a single phase scan was considered and performed in
others. The same authors tried to use masks in 2 dogs and
had to change immobilization systems to a vacuum cushion
during simulation CT.
The target of the procedure was different across the studies:
some works evaluated either left pulmonary veins alone (41) or
the right pulmonary veins (43, 45, 46), while 3 studies considered
both targets (42, 47). Zei et al. considered only the right superior
pulmonary vein as a target because of the excessive respiratory
motion of the left superior pulmonary vein in the canine model
(43). The follow-up ranged between 1 and 6 months. Efficacy
of radiotherapy ablation was generally confirmed at doses up to
about 25–30 Gy; side effects (i.e., bronchial-mediastinal fistula
with pneumonia and sepsis) were observed in one mini-swine
1 month after irradiation when the delivered dose exceeded
37.5 Gy (46). Moreover, one animal experienced a myocardial
infection following fiducial marker placement (43) and another
pericardial effusion (44). Mild side effects were mitral valve
regurgitation after the procedure in one case (42), one mild
reduction of ejection fraction (43), and electrocardiographic, self-
limiting abnormalities on T wave after anesthesia (4 animals)
(43). On the other hand, one animal died due to pericarditis after
electrophysiological study (45). Findings in animal studies were
usually evaluated by means of electroanatomic mapping, MRI
(46), or anatomopathological study after sacrificing the subjects.
A different approach was chosen by Gardner et al. (42),
where
the
implantable
metal
oxide
semiconductor
field-
effect
transistor
(MOSFET)
dose
verification
system
and
the thermoluminescent dosimetry in pulmonary vein antra
(PVA) isolation through CK technology were compared.
The authors observed that the implantation method adopted
for the MOSFET system shows a better concordance than
thermoluminescent dosimetry since it appears not to be
affected by body fluids. However, the difference between the
measured and the predicted doses in the MOSFET system
still accounts for almost 10% when the acceptance threshold
has been set at 5% by previous studies (48, 49). The authors
hypothesized that a degree of uncertainty might derive from
the impossibility to track the dose verification system during
treatment delivery.
Dosimetric Studies
In the category of dosimetric studies, a total of 122 treatment
plans on both photon radiotherapy (XRT) and PBT were
considered, with a median dose of 25 Gy (Table 2).
A dosimetric study is a preclinical work in which subjects
undergo simulation CT without experiencing radiation treatment
or in which the treatment plan is delivered to a phantom. These
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Stereotactic Ablation for Atrial Fibrillation
FIGURE 1 | Preferred reporting items for systematic reviews and meta-analyses flow-chart.
permit the evaluation of dosimetry in the target region and organs
at risk, avoiding any toxicity.
Meanly treatment plans consisted of one single fraction and
were delivered with CK in 2 cases (50, 51). Conversely, in
the other studies, a greater dose was planned with a CLA:
50 Gy in 5 fractions (10 Gy/fraction), according to the biological
effective dose (BED) (52, 53). According to Xia et al. (52), a
radiobiological modeling study (54) was used for BED calculation
with an alpha/beta ratio of 3 Gy; in the second study, Lydiard
et al. (53) did not explain how BED was evaluated and which
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Stereotactic Ablation for Atrial Fibrillation
TABLE 1 | Main characteristics of the preclinical studies on animals included in the analysis.
Study
Energy
N◦ subjects
Subjects
Total dose
(Gy)
N◦ of
fractions
Target
Fiducials
Accelerator
Respiratory
motion
control
Cardiac
motion
control
Delivered
plan
Follow-up
(months)
Efficacy
Toxicity
Blanck et al. (45)
XRT
9
Mini-pigs
15–35
1
RSPV
N/A
CLA
Yes
Yes
Yes
6
Dose
≥32.5 Gy
No
Bode et al. (46)
XRT
8
Mini-pigs
23–40
1
RSPV
No
CLA
Yes
Yes
Yes
6
Dose
≥30 Gy
Dose
≥37.5 Gy
Chang et al. (44)
XRT
7
Canines
33
1
WACA
N/A
CLA
Partially
No
Yes
2–4
50%
Pericardial
effusion
Gardner et al. (42)
XRT
4
Canines,
mini-pigs
20–35
1
PVA
Yes
CK
Yes
Yes
Yes
5
N/A
No
Maguire et al. (47)
XRT
2
Mini-pigs
25–35
1
PVA
Yes
CK
Yes
Yes
Yes
6
Yes
Trace
MVR
Sharma et al. (41)
XRT
4
Mini-pigs
38–40
1
LPV
Yes
CK
Yes
Yes
Yes
1–6
Yes
No
Zei et al. (43)
XRT
19
Canines,
mini-pigs
15–35
1
RSPV
Yes
CK
Yes
Yes
Yes
3–6
Dose
≥25 Gy
Min.
reduction
EF
CLA, conventional linear accelerator; CK, Cyberknife; EF, ejection fraction; LPV, left pulmonary vein; MVR, mitral valve regurgitation; N/A, not available; PVA, pulmonary vein antra; RSPV, right superior pulmonary vein;
WACA, wide area circumferential ablation; XRT, photon radiotherapy.
TABLE 2 | Main characteristics of the dosimetric photon and particle beam-based studies included in the analysis.
Study
Energy
N◦
subjects
Subjects
Total
dose
(Gy)
N◦ of
fractions
Target
Fiducials
Accelerator
Respiratory
motion
control
Cardiac
motion
control
Delivered
plan
Follow-up
(months)
Efficacy
Toxicity
Blanck et al. (50)
XRT
46
Humans
25
1
PVA
Yes
CK
Yes
Yes
No
N/A
N/A
N/A
Constantinescu et al. (58)
PBT
14
Humans
25–40
1
WACA
No
AA
Yes
Yes
No
N/A
N/A
N/A
Gardner et al. (51)
XRT
4
Humans
16–25
1
PVA ± LPW
No
CK
N/A
N/A
No
N/A
N/A
N/A
Ipsen et al. (55)
XRT
6
Humans
30
1
PVA
No
MRIL
Yes
Yes
No
N/A
N/A
N/A
Lehmann et al. (60)
PBT
3
Pigs
30–40
1
RSPV-LAJ
Yes
AA
Yes
Yes
Yes
6
Yes
No
Lydiard et al. (53)
XRT
15
Humans
50
5
PVA
No
CLA
Partially
Partially
Dynamic
phantom
N/A
N/A
N/A
Ren et al. (61)
XRT/PBT
11
Humans
25
1
WACA
No
AA/CLA
Yes
Yes
No
N/A
N/A
N/A
Richter et al. (59)
PBT
3
Pigs
30–40
1
RSPV-LAJ
Yes
AA
Yes
Yes
No
N/A
N/A
N/A
Xia et al. (52)
XRT
20
Humans
50
5
PVA
No
CLA
No
No
No
N/A
N/A
N/A
AA, adron accelerator; CLA, conventional linear accelerator; CK, Cyberknife; EF, ejection fraction; LPV, left pulmonary veins; LPW, left posterior wall; MRI, magnetic resonance imaging; MRIL, MRI-Linac, MRI-linear
accelerator; MVR, mitral valve regurgitation; N/A, not available; PBT, particle beam therapy; PVA, pulmonary vein antra; RSPV, right superior pulmonary vein; RSPV-LAJ, right superior pulmonary vein-left atrial junction;
WACA, wide area circumferential ablation; XRT, photon radiotherapy.
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Franzetti et al.
Stereotactic Ablation for Atrial Fibrillation
alpha/beta ratio considered. The prescription dose was delivered
to a dynamic phantom only in the study by Lydiard et al.
(53). Specifically, the authors registered the respiratory profiles
of 3 healthy patients and subsequently associated the recorded
profiles to the phantom to deliver plans differing in complexity.
The first was created using a dynamic conformal arc and a 3 mm
target volume (TV) margin expansion, one using volumetric
modulated arc therapy (VMAT) plan, a restricted number of
monitor unit and a 3-mm TV margin expansion, the other
VMAT plans with TV margin expansions of 0, 3, and 5 mm,
respectively. All dynamic plans were compared with the static
ones, and the superiority of multileaf collimator (MLC) tracking
over tracking without MLC was demonstrated, with a minor
failure percentage appreciated through a gamma failure rate, and
a better TV dose coverage.
Only Ipsen et al. (55) involved MRI-linear accelerator (MRI-
Linac) in their work: they evaluated the role of real-time MRI
target localization and efforted the treatment planning for cardiac
radiosurgery with MRI-Linac on 6 male volunteers.
The above-described preclinical studies considered PVA as the
only target of irradiation. Only Gardner et al. (51) compared 2
different target extensions: PVA and PVA plus left posterior wall
(LPW); the last one was optimized to spare mitral valve annulus,
right coronary, and circumflex arteries. Better compliance with
radiation therapy oncology group limits was observed in the
second target set, with the purpose to reduce the dose to the
ventricles where most cardiac adverse events after radiation
therapy would originate (56).
Overall, fiducials were implanted only by Blanck et al. (50);
in this work, the authors compared a spectrum of different
tracking systems: the partially invasive one, such as a catheter
in the right atrial septum (temporary fiducials), CK marker-less
tracking system for lung tumors (XSight
R⃝ Lung, Accuray) or
ultrasound tracking (50). In the same article, Blanck et al. (50)
described a prevalidation, contouring study comprising a series
of 133 patients’ CT scans: esophagus segmentation revealed that
in 50% of the cases the organ is directly in contact with the target,
similarly to transcatheter ablation (57).
Particle Beam Therapy
Four studies focused on PBT, and carbon ions were used in all
cases: 2 works were dosimetric (58, 59) and one reported on
in vivo dosimetry on animals (60). The last one (61) compared
intensity-modulated proton therapy with XRT delivered through
VMAT and helical tomotherapy.
Constantinescu et al. (58) evaluated 9 and 5 CT scans
of complete respiratory and cardiac cycles, respectively: they
planned 25–40 Gy single fraction carbon ion treatments
involving intensity-modulated particle therapy (IMPT). Authors
defined the importance of respiratory and heartbeat motions
with a lesion displacement of, respectively, ≤2 cm and <6 mm;
in this last case a worsening in dose coverage (V95 < 90%)
was registered. Carbon ion beam rescanning was used to
improve dose coverage.
The same rescanning technique was employed also by
Lehmann et al. (60) to reduce the interference between the
scanning motion of the beam and the target motion, the so-called
“interplay.” In their work, carbon ion irradiation in different TV
was evaluated: a 30–40 Gy single fraction treatment was delivered
on the right superior pulmonary vein-left atrial junction (RSPV-
LAJ) of 3 pigs; one of the 3 animals was irradiated with a lower
dose of 30 Gy to spare esophagus (due to specifical anatomy
of the animal), the others with 40 Gy. All the treatments were
delivered with in-beam positron emission tomography (PET) to
verify the correct deposition of carbon ions during irradiation. In
the end, they evaluated apoptotic markers employing the Western
blot technique with anti-caspase-3, antitubuline, and horseradish
peroxidase-conjugated secondary antibodies. As a result, they
found that an increase of these markers occurred 3 months
after the irradiation, but 6 months after the treatment all the
markers turned negative. With the same dataset, Richter et al. (59)
evaluated 17 treatment plans (3 on RSPV-LA, 14 on other targets)
with ECG-based-4D-dose reconstruction, showing higher safety
with respect to cardiac structures and efficient dose verification.
The most recent article included on PBT, Ren et al. (61),
evaluated dosimetric properties of intensity-modulated proton
therapy in comparison with VMAT and tomotherapy treatment
planning; the prescription dose was 25 Gy in all plans. The
proton-based technique resulted in a significantly reduce dose
in surrounding tissues, compared to photon-based ones, in
patients with AF.
Clinical Studies
Three of the selected studies considered human subjects, with
a total number of 6 patients (Table 3). The first clinical
work is a case report by Monroy et al. (62) on a 59-year-
old man with symptomatic AF suffering from adverse effects
caused by antiarrhythmic drugs and an ischemic stroke in
oral anticoagulant therapy. The need of performing catheter
manipulation within the left atrium, which is required by
classical PVI, was judged as a contraindication to a catheter-
based procedure. Therefore, a radio ablation was proposed
by the cardiologist, and the patient underwent radiosurgery,
delivered by CK in a single fraction, with a prescription dose
to pulmonary veins of 25 Gy to the 71% isodose line. Details
on the use of fiducials were not reported, and the details of
cardiac motion control. Respiratory motion was compensated by
synchrony image guidance during the whole course of treatment
delivery. Six months after the procedure the patient developed
a permanent AF requiring him to restart the medical therapy.
An MRI was performed 1 year the after procedure and a late
enhancement was recorded at the radio-ablated structure, which
may correspond to the development of a scar.
A second study [Qian et al. (63)] involved 2 patients with
symptomatic AF who had refused a catheter procedure and
had agreed to an experimental non-invasive ablation. Both had
undergone a fiducial placement and a subsequent simulation
contrast-enhanced CT scan. A prescription dose of 25 Gy was
delivered through a CK accelerator in both cases. Patients were
followed for 24 months (patient 1) and 48 months (patient
2), showing the absence of any significant treatment-related
side effects. Six months after irradiation, patient 1 developed
persistent AF, leading to permanent medical therapy. Conversely,
the second patient had no AF recurrences during the entire
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TABLE 3 | Main characteristics of the clinical studies included in the analysis.
Study
Energy
N◦
subjects
Total dose
(Gy)
N◦ of
fractions
Target
Fiducials
Accelerator
Respiratory
motion
control
Cardiac
motion
control
Delivered
plan
Follow-up
(months)
Efficacy
Toxicity
Monroy et al. (62)
XRT
1
25
1
PVA
N/A
CK
Yes
N/A
Yes
12
No
No
Qian et al. (63)
XRT
2
25–35
1
WACA
Yes
CK
Yes
Yes
Yes
48
50%
No
Shoji et al. (64)
XRT
3
22–30
1
WACA
Yes
CK
Yes
Yes
Yes
24
No
No
CK, Cyberknife; LPV, left pulmonary veins; N/A, not available; PVA, pulmonary vein antra; WACA, wide area circumferential ablation; XRT, photon radiotherapy.
follow-up. Only the second patient performed a pre- and post-
ablation MRI, showing evidence of a scar at the radiosurgery
site after 1 year.
The most recent article in the clinical area has been published
by Shoji et al. (64): 3 oncologic patients with refractory AF
were treated with a target dose of 25–30 Gy in a single fraction
delivered by CK. The TV was represented by a “box” lesion
set including a circumferential wide-area ablation (WACA) set
around pulmonary veins and the maximum follow-up was
24 months. One patient died 4 days after the procedure due to
oncologic disease. The autopsy revealed evidence of fibroblasts
and fibrogenesis in the region of radio-ablated tissues. On the
other two patients, who remained in AF, clear evidence of clinical
efficacy cannot be found: authors encountered some limitations
as a consequence of the second patient’s refusal to undergo
electrograms of LPW recorded from the esophagus. However,
the third patient underwent this exam and no atrial potentials
were seen from the esophageal electrogram recordings after radio
ablation. This evidence suggests an electrical block, which is
the clinical goal of the procedure. No acute or late effects were
registered during follow-up.
Gray Literature
Two of all the articles selected were gray literature: the first was
the preclinical study of Rahimian et al. (65) which included 3
patients’ treatment plans for a 25 Gy single fraction therapy.
The most recent study, Gregucci et al. (66) is currently enrolling
patients, and results are not yet available. All the studies
considered PVA as TV. No information about efficacy or toxicity
is now available from all this literature but it suggests the
increasing interest in this particular topic.
DISCUSSION
Main Evidence
Results from our work show the application of STAR for AF.
A prescription dose of at least 25 Gy in a single fraction
is necessary to have good efficacy despite an acceptable
toxicity profile.
The major cause of failure of traditional catheter ablation of
AF is incomplete circumferential vein isolation (9). It is worth
considering that, according to the existing literature on catheter
ablation, the choice of the target (11) and the circumferential scar
(67) is essential to obtain an effective procedure. Target selection
appears to have the same importance in non-invasive cardio-
ablation procedures, as confirmed by target heterogeneity among
considered studies (see section “Results”).
Target motion control, involving fiducials or other simulation
strategies (4DCT and cardio-CT or electroanatomic mapping) is
deemed necessary to improve the accuracy of the procedure.
It is worth saying that, despite the interest in the topic, a
limited number of humans has currently undergone STAR for AF
and only 2 articles including more than one patient have been
published (63, 64). In the study of Quian et al. (63), efficacy was
observed in one of 2 treated patients, but no detail on treatment
plan features was provided by the authors; moreover, 2 different
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Stereotactic Ablation for Atrial Fibrillation
pathways of preprocedural and follow-up exams were applied,
which cannot be considered as being completely comparable.
The absence of toxicity was the only shared feature between the
patients included. In the study of Shoji et al. (64), no acute or late
effects were observed; nevertheless, the choice to select oncologic
patients makes it more difficult to evaluate the endpoint of
efficacy. Even if clinical efficacy on human subjects is difficult
to be defined in a limited sample, fibrosis (63, 64), or electrical
block (64) was observed in the radio-ablated area in both studies.
A similar finding, obtained by an MRI exam, was recorded in
the case report (62). All the above-mentioned evidence may be
interpreted as the confirmation of the radio-ablation lesion.
In
conclusion,
available
evidence
reports
acceptable
tolerability
of
the
cardio-ablation
treatment
on
humans;
further analyses, together with the newest results coming from
the current “gray literature,” however, are deemed necessary to
reach the highest level of efficacy.
Validation of Stereotactic Arrhythmia
Radio Ablation With Regard to Different
Experimental Settings
We observed a prevalence of preclinical studies, the majority of
which involved mini pigs. This choice can be explained by their
relative growth stability and the consequent capability of weight
maintenance during follow-up. Three of the analyzed studies also
considered a canine model (42–44). However, regardless of the
chosen animal models (68), transferability concerns for clinical
applications in humans exist. Significant examples may be the
incomplete pericardium of dogs (47) or the different cardiac
chambers anatomy and number of pulmonary veins in humans
and canines (44). Specifically, these anatomical peculiarities could
affect respiratory and cardiac target motions, which are essential
parameters in treatment planning.
When evaluating the preclinical studies on animals it has been
shown that the efficacy is higher when mini pigs (41, 47) are
treated as compared with canines (44) or mixed samples (42).
Total prescription doses in the considered works ranged from
15 to 50 Gy/fraction and the minimum dose threshold for
efficacy was 25 Gy. Most of the studies encompassed stereotactic
radiosurgery delivered in a single fraction except for few articles
describing 5-fraction treatments with a dose of 10 Gy/fraction
(total dose: 50 Gy). This comparability is based on the BED which
was calculated by the authors (52) using a radiobiological model
to avoid the overestimation of the total dose resulting from the
linear-quadratic BED calculation when the dose is greater than
8–10 Gy (69). Of note, even if BEDs were considered comparable,
the heart tissue is a late responder and its alpha/beta ratio is about
3 Gy (31, 52) with the consequence that the effect may be superior
with higher doses delivered in a single fraction than with lower
fractionated doses.
A discrete number of studies based on the treatment plan
evaluation or delivery of the treatment on a dynamic phantom
can be found in the literature: even if they appear to be more
acceptable from the ethical standpoint, someone may question
if the evidence acquired from these studies are comparable, in
terms of efficacy and safety, with those acquired from the clinical
setting; in some cases (53), authors started from a study of
cardiac and respiratory montions on healthy patients, raising the
question whether the respiratory and cardiac motions are really
comparable in healthy patients with AF, as discussed below.
Role of the Target Motion
The role of the target motion was furthermore discussed in
almost all studies. This topic gains importance since the natural
motion of the organs influences not only the myocardial or the
conduction tissue around the target but also the other organs at
risk, the most important one appearing to be the esophagus. The
problem of organ motion was solved by some authors (50, 59, 60)
by adopting different fiducials such as seeds or catheters, whereas
other ones did not (46, 51–53). The presence of fiducials makes
the tracking useful in the positioning of the patient and in the
reduction of the margin of error due to cardiac and respiratory
motion, but it implies the use of tools that are against the peculiar
nature of the procedure in terms of non-invasiveness.
Grimm et al. (70) and Abelson et al. (71) faced the problem
of organs at risk doses by reviewing literature and patients’ data,
respectively, and elaborated dosimetric tables as references for the
colleagues’ work.
In the end, it is important to remember how it is possible
that a dilated heart with AF appears to have less movement than
a healthy one (61, 72): so, it is also possible that all dosimetric
studies on healthy subjects are not completely suitable for the
patients with real-AF and more investigations could be necessary.
At last, it is worth noticing the interesting application of MRI
to approach the problem of target motion (55, 73): on the one
hand, by quantifying target motion ranges on MRI, on the other
hand by analyzing the dosimetric benefits of margin reduction
assuming the application of real-time motion compensation.
Supporting this hypothesis, a recent article by Lydiard
et al. (74), not included in the selection, investigated the
feasibility of non-invasive MRI-guided tracking of cardiac-
induced target motion in AF cardiac radio ablation by comparing
a direct tracking method and 2 indirect tracking methods
(tracking indirect left atrial or other targets). They suggested
the applicability of non-invasive MRI-guided tracking, showing
a potential improvement in treatment efficacy.
Particle Beam Therapy: Pros and
Prospectives
Both XRT and PBT involve ionizing radiations, but the second
one can deliver its maximum dose at a specific depth (Bragg peak,
Figure 2) to the TV while no dose in the surrounding tissues (75).
Carbon ion should be particularly indicated for the aim of
cardio ablation because of the favorable RBE (three times as much
as the photons’ one) and the possibility of smaller beam foci and
less lateral scattering.
In the included articles, pencil beams were used to better
modulate the beam on the TV; the limit of these thin rays is a
major sensibility to motion and setup errors, then the correct
position of the beam’s distal edge remains unknown (75). Ren
et al. (61) decided to study this phenomenon in their work using
a cardiac motion scan from a patient case. Nevertheless, beam
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Stereotactic Ablation for Atrial Fibrillation
FIGURE 2 | Bragg peak in PBT. Reprinted from Mustapha et al. (81) with the
permission of AIP Publishing.
rescanning and 4D dose calculation (58) or the use of in-beam
PET can reduce the problem (60).
An interesting biological hypothesis about the effectiveness
of carbon ions in arrhythmia ablation was formulated by
Amino et al. (76): they studied the role of the upregulation of
connexin-43, a protein expressed during myocardial remodeling
in myocardial infarction or cardiac hypertrophy. This remodeling
effect on gap junctions may reduce the conduction of the
arrhythmia through myocardial tissue.
Although photons and carbon ions are so different, according
to the articles selected, the time to detect a scar in an
anatomopathological analysis is similar and it spans from weeks
to months. As further evidence, the process of fibrosis and scar
creation starts after the activation of the apoptotic cascade (77,
78), according to Lehmann et al.’s results (60).
Use of Stereotactic Arrhythmia Radio
Ablation in Atrial Fibrillation Versus
Ventricular Tachycardia
During the evaluation of the efficacy and safety of STAR in
AF, some considerations about the comparison between AF and
VT are necessary. First, it is worth underlying that specific
peculiarities characterize the anatomical and structural substrate
for AF as for VT, which reflect in different treatment approaches
and need to safeguard surrounding healthy structures. For
these reasons, some assumptions that have been preliminarily
validated in the field of VT may not be true for AF. Ventricular
arrhythmias, that may deserve STAR, are usually life-threatening;
patients present with recurrent and/or refractory VTs and are
not eligible for conventional approaches or these have proven
ineffective. In this clinical setting, STAR represents a promising
option, thus more risks, even unknown ones, are allowed. To
the best of our knowledge, in literature few severe adverse
events, definitely correlated to STAR, are reported. In particular,
one patient died of esophagopericardial fistula after 9 months
from STAR: of note, the patient had previous bypass surgery
with a gastroepiploic artery that might have contributed to this
severe adverse event (79); few clinically relevant or symptomatic
radiation-induced pericarditis and pericardial effusion and a
gastropericardial fistula 2 years after STAR were recorded (80).
Being AF a benign arrhythmia, more attention to the safety
rather than the efficacy of STAR is mandatory.
In this setting, more information about the toxicity profile of
this new approach is compulsory before applying STAR to AF
in clinical practice; this is also the reason why not many clinical
articles are available in the literature so far.
Strengths and Limitations
All the above-mentioned works and other already published
reviews discuss every type of tachydysrhythmias without a
specific focus on AF. The strength of this review is the specificity
of the topic treated: stereotactic radio ablation of AF through both
XRT and PBT. In this regard, we would like to underline once
again that these considerations do not necessarily apply to other
patients’ conditions (e.g., non-oncological patients).
The main limitations of this work are the relative paucity of
works, which is in line with the novelty of the field, and the low
evidence of available literature. Moreover, given the nature of
our work (qualitative rather than quantitative synthesis), and the
relative paucity of studies, it was not possible to fully estimate
publication bias—if any—through a funnel plot. To at least
account for such potential weakness, gray literature was also
included. As a matter of fact, while these works are not peer-
reviewed, good-quality gray literature is a source of up-to-date
information on ongoing clinical efforts.
CONCLUSION
Stereotactic
radio
ablation
is
an
innovative
non-invasive
procedure already in use for ventricular cardiac arrhythmias.
Radio ablation of AF, with a prescription dose at least of 25 Gy,
might be considered among the future therapeutic option for
AF, especially when an interventional ablation procedure is
contraindicated or proved ineffective.
Carbon ions are a highly promising radiation technique due to
their TV coverage and, at the same time, their greater capability
to spare organs at risk; this may be a strong point to achieve an
effective safer alternative application for the heart.
Essential issues, such as:
– duration of AF before treatment,
– target definition and motion, and
– doses delivered to the target and organs at risk,
deserve further evaluation to define proper indications and
modalities to benefit the most from the use of STAR in
patients with AF.
DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included
in the article/Supplementary Material, further inquiries can be
directed to the corresponding author.
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May 2022 | Volume 9 | Article 849201
Franzetti et al.
Stereotactic Ablation for Atrial Fibrillation
AUTHOR CONTRIBUTIONS
JF contributed to conception of the study and wrote the first draft
of the manuscript. SV wrote the first draft of the manuscript
and was the third reviewer of the literature. VC performed the
literature research and contributed to write the first draft of the
manuscript. CP was the first reviewer of the literature. EC, GP,
and FC contributed to write sections of the manuscript. MP
designed and prepared the tables. AMC was the second reviewer
of the literature. DA and CT critically revised the final version.
BAJ-F contributed to conception of the study and critically
revised the final version. CC designed the study and contributed
to wrote the first draft of the manuscript and the final revision. All
authors contributed to manuscript revision, read, and approved
the submitted version.
FUNDING
SV was partially supported by the Italian Ministry of Health
with Progetto di Eccellenza. SV was a Ph.D. student at the
European School of Molecular Medicine (SEMM), Milan. CP
was supported by a research grant from the Fondazione IEO-
CCM entitled “STereotactic Radio Ablation by Multimodal
Imaging for Ventricular Tachycardia (STRA-MI-VT)” and by
a research grant from the AIRC entitled “Phase I/II clinical
trial on single fraction ablative preoperative radiation treatment
for early-stage breast cancer.” The institutions IEO IRCCS and
CCM IRCCS are partially supported by the Italian Ministry
of Health with 5 × 1,000 funds and Ricerca Corrente (RC
2019—EF 5A—ID2754331 to Centro Cardiologico Monzino
IRCCS). The sponsors did not play any role in the study design,
collection, analysis, and interpretation of data, in the writing of
the manuscript, or in the decision to submit the manuscript for
publication.
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online
at:
https://www.frontiersin.org/articles/10.3389/fcvm.
2022.849201/full#supplementary-material
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